Polymers of fluorinated monomers and hydrophilic monomers

ABSTRACT

A polymer of fluorinated monomers and hydrophilic monomers is provided. It is also provided a polymer blend that contains a polymer of fluorinated monomers and another biocompatible polymer. The polymer of fluorinated monomers or polymer blend described herein and optionally a bioactive agent can form a coating on an implantable device such as a drug-delivery stent. The implantable device can be used for treating or preventing a disorder such as atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, patent foramen ovale, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, or combinations thereof.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention generally relates to a polymeric material useful forcoating an implantable device, such as a stent.

2. Description of the Background

Although stents work well mechanically, the chronic issues of restenosisand, to a lesser extent, stent thrombosis remain. Pharmacologicaltherapy in the form of a drug-delivery stent appears a feasible means totackle these biologically derived issues. Polymeric coatings placed ontothe stent serve to act both as the drug reservoir, and to control therelease of the drug. One of the commercially available polymer coatedproducts is stents manufactured by Boston Scientific. For example, U.S.Pat. Nos. 5,869,127; 6,099,563; 6,179,817; and 6,197,051, assigned toBoston Scientific Corporation, describe various compositions for coatingmedical devices. These compositions provide to stents described thereinan enhanced biocompatibility and may optionally include a bioactiveagent. U.S. Pat. No. 6,231,590 to Scimed Life Systems, Inc., describes acoating composition, which includes a bioactive agent, a collagenousmaterial, or a collagenous coating optionally containing or coated withother bioactive agents.

The nature of the coating polymers plays an important role in definingthe surface properties of a coating. For example, a very low T_(g),amorphous coating material can have unacceptable rheological behaviorupon mechanical perturbation such as crimping, balloon expansion, etc.On the other hand, a high T_(g), or highly crystalline coating materialintroduces brittle fracture in the high strain areas of the stentpattern.

A current paradigm in biomaterials is the control of protein adsorptionon the implant surface. Uncontrolled protein adsorption, leading tomixed layer of partially denatured proteins, is a hallmark of currentbiomaterials when implanted. Such a surface presents different cellbinding sites from adsorbed plasma proteins such as fibrogen andimmunogloblulin G. Platelets and inflammatory cells such asmonocyte/macrophages and neutrophils adhere to these surfaces.Unfavorable events can be controlled by the use of non-fouling surfaces.These are materials, which absorb little or no protein, primarily due totheir hydrophilic surface properties.

Another limitation of current drug-delivery stents stems from the factthat the stent is a foreign body. Use of drug-delivery stents has provedsuccessful by use of controlled release of anti-proliferative oranti-inflammatory drugs to control restenosis. However, drug-deliverystents still have a small, but measurable, incidence of sub-acutethrombosis. Moreover, drug-delivery stents have not driven restenosis tozero levels, especially in more challenging patient subsets such asdiabetics or patients with small vessels, and/or long, diffuse lesions.A biomaterials-based strategy for further improving the outcome ofdrug-delivery stents is by the use of biobeneficial materials orsurfaces in stent coatings. A biobeneficial material is one whichenhances the biocompatibility of a device by being non-fouling,hemocompatible, actively non-thrombogenic, or anti-inflammatory, allwithout depending on the release of a pharmaceutically active agent.

Some of the currently used polymeric materials such aspoly(vinylidene-co-hexafluoropropene) have good mechanical properties,and acceptable biocompatibility, but also have low permeability todrugs. One proposed solution to ameliorate this issue is to blend inhydrophilic polymers. However, it is well known in the art that manyhydrophilic materials such as polyethylene oxide or hyaluronic acid arewater-soluble and can be leached out of the composition such that thecoating may lose biobeneficiality. Such polymeric blends can also havecompromised mechanical properties, particularly the ultimate elongation.

The present invention addresses such problems by providing a polymericmaterial for coating implantable devices.

SUMMARY OF THE INVENTION

Provided herein is a polymer formed of fluorinated monomers andhydrophilic monomers. The fluorinated monomers can provide mechanicalstrength and/or flexibility, biocompatibility, and physiologic durablityfor the polymer. The hydrophilic monomers impart drug permeability tothe polymer, and can provide additional biobeneficial properties.

In one embodiment, the polymer can be a random or block polymer having ageneral formula as shown below (Formula I):

where m and n can be 0 or positive integers ranging from, e.g., 1 to100,000 and m+n≠0; and o can be a positive integer ranging from, e.g., 1to 100,000.

The strength fluoro monomers are generally fluorinated ethylene monomerssuch as —CF₂—CF₂—, —CH₂—CF₂—, —CH₂—CHF—, —CF₂—CHF—, —CHF—CHF—, orCF₂—CRF— where R can be phenyl, cyclic alkyl, heterocyclic, heteroaryl,fluorinated phenyl, fluorinated cyclic alkyl, or fluorinatedheterocyclic.

The flexibility fluoro monomers are generally substituted fluorinatedethylene monomers bearing a substituent (R), —CF₂—CRF—, —CHF—CRF—, and—CF₂—CRH—. R can be trifluoromethyl, F, Cl, Br, I, short chain alkylgroups from C₂ to C₁₂, fluorinated short chain alkyl groups from C₂ toC₁₂, and combinations thereof.

The hydrophilic monomers can be any vinyl monomer having pyrrolidonegroup(s), carboxylic acid group(s), sulfone group(s), sulfonic acidgroup(s), amino group(s), alkoxy group(s), amide group(s), estergroup(s), acetate group(s), poly(ethylene glycol) group(s),poly(propylene glycol) groups, poly(tetramethylene glycol) groups,poly(alkylene oxide), hydroxyl group(s), or a substituent that bears acharge and/or any of pyrrolidone group(s), carboxylic acid group(s),sulfone group(s), sulfonic acid group(s), amino group(s), alkoxygroup(s), amide group(s), ester group(s), acetate group(s),poly(ethylene glycol) group(s), poly(propylene glycol) group(s),poly(tetramethylene glycol) group(s), poly(alkylene oxide) group(s), andhydroxyl group(s). Some exemplary hydrophilic monomers are vinylpyrrolidone, hydroxyethyl methacrylate, hydroxypropyl methacrylate,methyl vinyl ether, alkyl vinyl ether, vinyl alcohol, methacrylic acid,acrylic acid, acrylamide, N-alkyl acrylamide,hydroxypropylmethacrylamide, vinyl acetate, 2-sulfoethyl methacrylate,3-sulfopropyl acrylate, 3-sulfopropyl methacrylate, andPEG-methacrylate. Some exemplary substituents bearing a charge can be,for example, choline, phosphoryl choline, 2-aminoethyl methacrylatehydrochloride, N-(3-aminopropyl)methacrylamide hydrochloride,2-N-morpholinoethyl methacrylate, vinylbenzoic acid, vinyl sulfonicacid, and styrene sulfonates.

The monomers for strength generally account for about 60 mole % to about90 mole % of the total monomers forming the polymer, the monomers forflexibility generally account for about 0 mole % to about 40 mole % ofthe total monomers forming the polymer, and the hydrophilic monomers forenhancing permeability generally account for about 0 mole % to about 20mole % of the total monomers forming the polymer. By varying the molepercentages of the three components of the polymer, one can fine-tunephysical properties of the polymer.

In another embodiment, it is provided a polymer blend that includes apolymer that has fluorinated monomers and at least one otherbiocompatible polymer. In one embodiment, the polymer that hasfluorinated monomers has a structure of formula I as defined above.

The polymer or polymer blends described herein can be used to form acoating(s) on an implantable device. The polymers or polymer blendsdescribed herein can also be used to form the implantable device itself.The implantable device can optionally include a bioactive agent. Someexemplary bioactive agents are paclitaxel, docetaxel, estradiol, nitricoxide donors, super oxide dismutases, super oxide dismutases mimics,4-amino-2,2,6,6-tetramethylpiperidine-1 -oxyl(4-amino-TEMPO),tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,ABT-578, clobetasol, prodrugs thereof, co-drugs thereof, andcombinations thereof. The implantable device can be implanted in apatient to treat or prevent a disorder such as atherosclerosis,thrombosis, restenosis, hemorrhage, vascular dissection or perforation,vascular aneurysm, vulnerable plaque, chronic total occlusion,claudicationanastomotic proliferation for vein and artificial grafts,bile duct obstruction, ureter obstruction, tumor obstruction, orcombinations thereof.

DETAILED DESCRIPTION Polymers of Fluorinated Monomers and HydrophilicMonomers

Provided herein is a polymer formed of fluorinated monomers andhydrophilic monomers. The fluorinated monomers can provide mechanicalstrength and/or flexibility, biocompatibility, and physiologic durablityfor the polymer. The hydrophilic monomers impart drug permeability tothe polymer, and can provide additional biobeneficial properties.

In one embodiment, the polymer can be a random or block polymer having ageneral formula as shown below (Formula I):

where m and n can be 0 or positive integers ranging from, e.g., 1 to100,000 and m+n≠0; and o can be a positive integer ranging from, e.g., 1to 100,000. The strength fluoro monomer can be in the range of, e.g.,from about 60 mole % to about 90 mole %, the flexibility fluoro monomercan be in the range of, e.g., from about 0 mole % to about 40 mole %,and the hydrophilic monomer can be in the range from above 0 mole % toabout 20 mole %.

The strength fluoro monomers are generally fluorinated ethylene monomerssuch as —CF₂—CF₂—, —CH₂—CF₂—, —CH₂—CHF—, —CF₂—CHF—, —CHF—CHF—, orCF₂—CRF— where R can be phenyl, cyclic alkyl, heterocyclic, heteroaryl,fluorinated phenyl, fluorinated cyclic alkyl, or fluorinatedheterocyclic.

The flexibility fluoro monomers are generally substituted fluorinatedethylene monomers bearing a substituent (R), —CF₂—CRF—, —CHF—CRF—, and—CF₂—CRH—. R can be trifluoromethyl, F, Cl, Br, I, short chain alkylgroups from C₂ to C₁₂, fluorinated short chain alkyl groups from C₂ toC₁₂, and combinations thereof.

The hydrophilic monomers can be any vinyl monomer having pyrrolidonegroup(s), carboxylic acid group(s), sulfone group(s), sulfonic acidgroup(s), amino group(s), alkoxy group(s), amide group(s), estergroup(s), acetate group(s), poly(ethylene glycol) group(s),poly(propylene glycol) group(s), poly(tetramethylene glycol) group(s),poly(alkylene oxide) group(s), hydroxyl group(s), or a substituent thatbears a charge and/or any of pyrrolidone group(s), carboxylic acidgroup(s), sulfone group(s), sulfonic acid group(s), amino group(s),alkoxy group(s), amide group(s), ester group(s), acetate group(s),poly(ethylene glycol) group(s), poly(propylene glycol) group(s),poly(tetramethylene glycol) group(s), poly(alkylene oxide) group(s), andhydroxyl group(s). Some exemplary hydrophilic monomers are vinylpyrrolidone, hydroxyethyl methacrylate, hydroxypropyl methacrylate,methyl vinyl ether, alkyl vinyl ether, vinyl alcohol, methacrylic acid,acrylic acid, acrylamide, N-alkyl acrylamide,hydroxypropylmethacrylamide, vinyl acetate, 2-sulfoethyl methacrylate,3-sulfopropyl acrylate, 3-sulfopropyl methacrylate, andPEG-methacrylate. Some exemplary substituents bearing a charge can be,for example, choline, phosphoryl choline, 2-aminoethyl methacrylatehydrochloride, N-(3-aminopropyl)methacrylamide hydrochloride,2-N-morpholinoethyl methacrylate, vinylbenzoic acid, vinyl sulfonicacid, and styrene sulfonates.

The monomers for strength generally account for about 60 mole % to about90 mole % of the total monomers forming the polymer, the monomers forflexibility generally account for about 0 mole % to about 40 mole % ofthe total monomers forming the polymer, and the hydrophilic monomers forenhancing permeability generally account for about 0 mole % to about 20mole % of the total monomers forming the polymer. By varying the molepercentages of the three components of the polymer, one can fine-tunephysical properties of the polymer.

In some embodiments, the polymer of formula I has a structure of formulaII or formula III:

The vinyl pyrrolidone is known to be miscible with the vinylidenefluoride as both have strong dipolar interactions. Therefore, there isnot a large driving force for phase separation. The vinylidene fluoridehas a propensity to crystallize and, therefore provides the strength forthe polymer. This strength can be tuned by the amount ofhexafluoropropene, which lowers the crystallinity and promotes theflexibility of the polymer. The pyrrolidone is a hydrophilic monomer andwill increase the water absorption of the polymer. Water absorption ofthe polymer strongly influences the drug permeability of the polymer.For example, poly(vinylidene fluoride-co-hexafluoropropene) has a verylow water absorption of <0.04 w %, and it has a low drug permeability.Addition of small amounts of vinyl pyrrolidone in the range betweenabout 1 mole % to about 10 mole % will appreciably alter drugpermeability of the polymer.

In formula III, the pyrrolidone would inhibit the crystallization of thevinylidene fluoride monomers, which will increase the flexibility of thepolymer. The pyrrolidone group would also impart hydrophilicity to thepolymer, thereby increasing drug permeability of the polymer.

In another embodiment, the polymer of formula I has a structure offormula IV:

In this polymer, the tetrafluoroethylene monomer imparts strength to thepolymer, and the hexafluoropropene monomer provides flexibility to thepolymer. The hydrophilicity of the polymer can be tuned by the amount of3-hydroxypropyl methacrylate. In addition, with an adequate amount of3-hydroxypropyl methacrylate, in the range of 5–25 mole %, incorporatedin to a terpolymer with 5–15 mole % hexafluoropropene, this polymer canbe made solvent soluble.

The polymers described herein can be synthesized by methods known in theart (see, for example, D. Braun, et al., Polymer Synthesis: Theory andPractice. Fundamentals, Methods, Experiments. 3^(rd) Ed., Springer,2001; Hans R. Kricheldorf, Handbook of Polymer Synthesis, Marcel DekkerInc., 1992; G. Odian, Principles of Polymerization, 3^(rd) ed. JohnWiley & Sons, 1991). For example, one method that can be used to makethe polymer can be free radical methods (see, for example, D. Braun, etal., Polymer Synthesis: Theory and Practice. Fundamentals, Methods,Experiments. 3^(rd) Ed., Springer, 2001; Hans R. Kricheldorf, Handbookof Polymer Synthesis, Marcel Dekker Inc., 1992). Polymerization bysuspension or emulsion techniques utilizing free radical initiation iscommonly employed. Block copolymers and terpolymers can be produced byatom transfer polymerization. Grafting of hydrophilic monomers ontopre-made poly(vinylidene fluoride-co-hexafluoropropylene) can beaccomplished by ozonation of the fluoropolymer followed by thermallyinduced graft polymerization of the hydrophilic monomer. Polymerizationin solvent can also be used to synthesize the polymers described herein.

Polymer Blends

In another embodiment, a hydrophobic polymer of fluorinated monomerssuch as polyvinylidene fluoride (PDVF) or poly(vinylidenefluoride-co-hexafluoropropylene) (PVDF-co-HFP) can be blended with oneor more additional biocompatible polymers having differenthydrophilicity and/or flexibility to generate a polymer blend coatingmaterial that has desired flexibility and drug permeability. Generally,useful polymers that can be blended with the polymer of fluorinatedmonomers are substantially miscible with the polymer of fluorinatedmonomers. In a further embodiment, any of the polymers of formulae I-IVcan be blended with one or more additional biocompatible polymer, whichis described below.

The additional biocompatible polymer can be biodegradable (bothbioerodable or bioabsorbable) or nondegradable, and can be hydrophilicor hydrophobic. Hydrophilic is defined to have a δ value greater thanabout 8.5, e.g., a δ value of about 8.5, about 9.5, about 10.5 or about11.5.

Representative biocompatible polymers include, but are not limited to,poly(ester amide), polyhydroxyalkanoates (PHA),poly(3-hydroxyalkanoates) such as poly(3-hydroxypropanoate), poly(3-hydroxybutyrate), poly(3 -hydroxyvalerate), poly(3-hydroxyhexanoate),poly(3-hydroxyheptanoate) and poly(3 -hydroxyoctanoate),poly(4-hydroxyalkanaote) such as poly(4-hydroxybutyrate),poly(4-hydroxyvalerate), poly(4-hydroxyhexanote),poly(4-hydroxyheptanoate), poly(4-hydroxyoctanoate) and copolymersincluding any of the 3-hydroxyalkanoate or 4-hydroxyalkanoate monomersdescribed herein or blends thereof, poly polyesters, poly(D,L-lactide),poly(L-lactide), polyglycolide, poly(D,L-lactide-co-glycolide),poly(L-lactide-co-glycolide), polycaprolactone,poly(lactide-co-caprolactone), poly(glycolide-co-caprolactone),poly(dioxanone), poly(ortho esters), poly(anhydrides), poly(tyrosinecarbonates) and derivatives thereof, poly(tyrosine ester) andderivatives thereof, poly(imino carbonates), poly(glycolicacid-co-trimethylene carbonate), polyphosphoester, polyphosphoesterurethane, poly(amino acids), polycyanoacrylates, poly(trimethylenecarbonate), poly(iminocarbonate), polyurethanes, polyphosphazenes,silicones, polyesters, polyolefins, polyisobutylene andethylene-alphaolefin copolymers, acrylic polymers and copolymers, vinylhalide polymers and copolymers, such as polyvinyl chloride, polyvinylethers, such as polyvinyl methyl ether, polyvinylidene halides, such aspolyvinylidene chloride, polyacrylonitrile, polyvinyl ketones, polyvinylaromatics, such as polystyrene, polyvinyl esters, such as polyvinylacetate, copolymers of vinyl monomers with each other and olefins, suchas ethylene-methyl methacrylate copolymers, acrylonitrile-styrenecopolymers, ABS resins, and ethylene-vinyl acetate copolymers,polyamides, such as Nylon 66 and polycaprolactam, alkyd resins,polycarbonates, polyoxymethylenes, polyimides, polyethers, poly(glycerylsebacate), poly(propylene fumarate), poly(n-butyl methacrylate),poly(sec-butyl methacrylate), poly(isobutyl methacrylate),poly(tert-butyl methacrylate), poly(n-propyl methacrylate),poly(isopropyl methacrylate), poly(ethyl methacrylate), poly(methylmethacrylate), epoxy resins, polyurethanes, rayon, rayon-triacetate,cellulose acetate, cellulose butyrate, cellulose acetate butyrate,cellophane, cellulose nitrate, cellulose propionate, cellulose ethers,carboxymethyl cellulose, polyethers such as poly(ethylene glycol) (PEG),copoly(ether-esters) (e.g. PEO/PLA); polyalkylene oxides such aspoly(ethylene oxide), poly(propylene oxide), poly(ether ester),polyalkylene oxalates, polyphosphazenes, phosphoryl choline, choline,poly(aspirin), polymers and co-polymers of hydroxyl bearing monomerssuch as HEMA, hydroxypropyl methacrylate (HPMA),hydroxypropylmethacrylamide, PEG acrylate (PEGA), PEG methacrylate,2-methacryloyloxyethylphosphorylcholine (MPC) and N-vinyl pyrrolidone(VP), carboxylic acid bearing monomers such as methacrylic acid (MA),acrylic acid (AA), alkoxymethacrylate, alkoxyacrylate, and3-trimethylsilyipropyl methacrylate (TMSPMA),poly(styrene-isoprene-styrene)-PEG (SIS-PEG), polystyrene-PEG,polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG,poly(methyl methacrylate)-PEG (PMMA-PEG), polydimethylsiloxane-co-PEG(PDMS-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), PLUIRONIC™surfactants (polypropylene oxide-co-polyethylene glycol),poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone),biomolecules such as collagen, chitosan, alginate, fibrin, fibrinogen,cellulose, starch, collagen, dextran, dextrin, fragments and derivativesof hyaluronic acid, heparin, fragments and derivatives of heparin,glycosamino glycan (GAG), GAG derivatives, polysaccharide, elastin,chitosan, alginate, and combinations thereof. In some embodiments, thepolymer can exclude any one of the aforementioned polymers.

As used herein, the terms poly(D,L-lactide), poly(L-lactide),poly(D,L-lactide-co-glycolide), and poly(L-lactide-co-glycolide) can beused interchangeably with the terms poly(D,L-lactic acid), poly(L-lacticacid), poly(D,L-lactic acid-co-glycolic acid), and poly(L-lacticacid-co-glycolic acid), respectively.

Biobeneficial Material

The copolymer of fluorinated monomers and hydrophilic monomers can forma coating optionally with a biobeneficial material. The combination canbe mixed, blended, or coated in separate layers. The biobeneficialmaterial useful in the coatings described herein can be a polymericmaterial or non-polymeric material. The biobeneficial material ispreferably non-toxic, non-antigenic and non-immunogenic. A biobeneficialmaterial is one which enhances the biocompatibility of a device by beingnon-fouling, hemocompatible, actively non-thrombogenic, oranti-inflammatory, all without depending on the release of apharmaceutically active agent.

Representative biobeneficial materials include, but are not limited to,polyethers such as poly(ethylene glycol); copoly(ether-esters) (e.g.PEO/PLA); polyalkylene oxides such as poly(ethylene oxide),poly(propylene oxide), poly(ether ester), polyalkylene oxalates,polyphosphazenes, phosphoryl choline, choline, poly(aspirin), polymersand co-polymers of hydroxyl bearing monomers such as hydroxyethylmethacrylate (HEMA), hydroxypropyl methacrylate (HPMA),hydroxypropylmethacrylamide, poly (ethylene glycol) acrylate (PEGA), PEGmethacrylate, 2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinylpyrrolidone (VP), carboxylic acid bearing monomers such as methacrylicacid (MA), acrylic acid (AA), alkoxymethacrylate, alkoxyacrylate, and3-trimethylsilylpropyl methacrylate (TMSPMA),poly(styrene-isoprene-styrene)-PEG (SIS-PEG), polystyrene-PEG,polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG,poly(methyl methacrylate)-PEG (PMMA-PEG), polydimethylsiloxane-co-PEG(PDMS-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), PLURONIC™surfactants (polypropylene oxide-co-polyethylene glycol),poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone),biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen,dextran, dextrin, hyaluronic acid, fragments and derivatives ofhyaluronic acid, heparin, fragments and derivatives of heparin,glycosamino glycan (GAG), GAG derivatives, polysaccharide, elastin,chitosan, alginate, silicones, PolyActive™, and combinations thereof. Insome embodiments, the coating can exclude any one of the aforementionedpolymers.

The term PolyActive™ refers to a block copolymer having flexiblepoly(ethylene glycol) and poly(butylene terephthalate) blocks(PEGT/PBT). PolyActive™ is intended to include AB, ABA, BAB copolymershaving such segments of PEG and PBT (e.g., poly(ethyleneglycol)-block-poly(butyleneterephthalate)-block-poly(ethylene glycol)(PEG-PBT-PEG)).

In a preferred embodiment, the biobeneficial material can be a polyethersuch as poly (ethylene glycol) (PEG) or polyalkylene oxide.

Bioactive Agents

The polymeric coatings or the polymeric substrate described herein mayoptionally include one or more bioactive agents. These bioactive agentscan be any agent which is a therapeutic, prophylactic, or diagnosticagent. These agents can have anti-proliferative or anti-inflammatoryproperties or can have other properties such as antineoplastic,antiplatelet, anti-coagulant, anti-fibrin, antithrombonic, antimitotic,antibiotic, antiallergic, antioxidant as well as cystostatic agents.Examples of suitable therapeutic and prophylactic agents includesynthetic inorganic and organic compounds, proteins and peptides,polysaccharides and other sugars, lipids, and DNA and RNA nucleic acidsequences having therapeutic, prophylactic or diagnostic activities.Nucleic acid sequences include genes, antisense molecules which bind tocomplementary DNA to inhibit transcription, and ribozymes. Some otherexamples of other bioactive agents include antibodies, receptor ligands,enzymes, adhesion peptides, blood clotting factors, inhibitors or clotdissolving agents such as streptokinase and tissue plasminogenactivator, antigens for immunization, hormones and growth factors,oligonucleotides such as antisense oligonucleotides and ribozymes andretroviral vectors for use in gene therapy. Examples ofanti-proliferative agents include rapamycin and its functional orstructural derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),and its functional or structural derivatives, paclitaxel and itsfunctional and structural derivatives. Examples of rapamycin derivativesinclude methyl rapamycin (ABT-578), 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.Examples of paclitaxel derivatives include docetaxel. Examples ofantineoplastics and/or antimitotics include methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g.Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples ofsuch antiplatelets, anticoagulants, antifibrin, and antithrombinsinclude sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, thrombin inhibitorssuch as Angiomax ä (Biogen, Inc., Cambridge, Mass.), calcium channelblockers (such as nifedipine), colchicine, fibroblast growth factor(FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists,lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol loweringdrug, brand name Mevacor® from Merck & Co., Inc., Whitehouse Station,N.J.), monoclonal antibodies (such as those specific forPlatelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), nitric oxide or nitric oxidedonors, super oxide dismutases, super oxide dismutase mimetic,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), estradiol,anticancer agents, dietary supplements such as various vitamins, and acombination thereof. Examples of anti-inflammatory agents includingsteroidal and non-steroidal anti-inflammatory agents include tacrolimus,dexamethasone, clobetasol, combinations thereof. Examples of suchcytostatic substance include angiopeptin, angiotensin converting enzymeinhibitors such as captopril (e.g. Capoten® and Capozide® fromBristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril(e.g. Prinivil® and Prinzide® from Merck & Co., Inc., WhitehouseStation, N.J.). An example of an antiallergic agent is permirolastpotassium. Other therapeutic substances or agents which may beappropriate include alpha-interferon, bioactive RGD, and geneticallyengineered epithelial cells. The foregoing substances can also be usedin the form of prodrugs or co-drugs thereof. The foregoing substancesare listed by way of example and are not meant to be limiting. Otheractive agents which are currently available or that may be developed inthe future are equally applicable.

The dosage or concentration of the bioactive agent required to produce afavorable therapeutic effect should be less than the level at which thebioactive agent produces toxic effects and greater than the level atwhich non-therapeutic results are obtained. The dosage or concentrationof the bioactive agent can depend upon factors such as the particularcircumstances of the patient; the nature of the trauma; the nature ofthe therapy desired; the time over which the ingredient administeredresides at the vascular site; and if other active agents are employed,the nature and type of the substance or combination of substances.Therapeutic effective dosages can be determined empirically, for exampleby infusing vessels from suitable animal model systems and usingimmunohistochemical, fluorescent or electron microscopy methods todetect the agent and its effects, or by conducting suitable in vitrostudies. Standard pharmacological test procedures to determine dosagesare understood by one of ordinary skill in the art.

Examples of Implantable Device

As used herein, an implantable device may be any suitable medicalsubstrate that can be implanted in a human or veterinary patient.Examples of such implantable devices include self-expandable stents,balloon-expandable stents, stent-grafts, grafts (e.g., aortic grafts),artificial heart valves, cerebrospinal fluid shunts, pacemakerelectrodes, and endocardial leads (e.g., FINELINE and ENDOTAK, availablefrom Guidant Corporation, Santa Clara, Calif.). The underlying structureof the device can be of virtually any design. The device can be made ofa metallic material or an alloy such as, but not limited to, cobaltchromium alloy (ELGILOY), stainless steel (316L), high nitrogenstainless steel, e.g., BIODUR 108, cobalt chrome alloy L-605, “MP35N,”“MP20N,” ELASTINITE (Nitinol), tantalum, nickel-titanium alloy,platinum-iridium alloy, gold, magnesium, or combinations thereof.“MP35N” and “MP20N” are trade names for alloys of cobalt, nickel,chromium and molybdenum available from Standard Press Steel Co.,Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20%chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum. Devices made frombioabsorbable or biostable polymers could also be used with theembodiments of the present invention. The device itself, such as astent, can also be made from the described inventive polymers or polymerblends.

Method of Use

In accordance with embodiments of the invention, a coating of thevarious described embodiments can be formed on an implantable device orprosthesis, e.g., a stent. For coatings including one or more activeagents, the agent will retain on the medical device such as a stentduring delivery and expansion of the device, and released at a desiredrate and for a predetermined duration of time at the site ofimplantation. Preferably, the medical device is a stent. A stent havingthe above-described coating is useful for a variety of medicalprocedures, including, by way of example, treatment of obstructionscaused by tumors in bile ducts, esophagus, trachea/bronchi and otherbiological passageways. A stent having the above-described coating isparticularly useful for treating occluded regions of blood vesselscaused by abnormal or inappropriate migration and proliferation ofsmooth muscle cells, thrombosis, and restenosis. Stents may be placed ina wide array of blood vessels, both arteries and veins. Representativeexamples of sites include the iliac, renal, and coronary arteries.

For implantation of a stent, an angiogram is first performed todetermine the appropriate positioning for stent therapy. An angiogram istypically accomplished by injecting a radiopaque contrasting agentthrough a catheter inserted into an artery or vein as an x-ray is taken.A guidewire is then advanced through the lesion or proposed site oftreatment. Over the guidewire is passed a delivery catheter which allowsa stent in its collapsed configuration to be inserted into thepassageway. The delivery catheter is inserted either percutaneously orby surgery into the femoral artery, brachial artery, femoral vein, orbrachial vein, and advanced into the appropriate blood vessel bysteering the catheter through the vascular system under fluoroscopicguidance. A stent having the above-described coating may then beexpanded at the desired area of treatment. A post-insertion angiogrammay also be utilized to confirm appropriate positioning.

EXAMPLES

The embodiments of the present invention will be illustrated by thefollowing set forth prophetic examples. All parameters and data are notto be construed to unduly limit the scope of the embodiments of theinvention.

Example 1 Synthesis of poly(vinylidenefluoride-co-hexafluoropropylene-co-vinyl pyrrolidone), 80/15/5 MolarRatio

A 20 gallon glass lined autoclave is filled with 11 gallons of deionizedwater, and then sparged with nitrogen to remove oxygen. The autoclavedis then charged with 3.47 kg of vinylidene fluoride (VDF) and 1.53 Kg ofhexafluoropropylene (HFP). 40 g of a 70% solution of tertiary butylhydroperoxide in water is diluted to 250 ml with deionized water. 31 gof sodium metabisulfite and 6.3 g of ferrous sulfate heptahydrate isdiluted to 250 ml with deionized water. These two solutions are addedseparately to the autoclave over a ten period time period. The autoclaveis maintained throughout the entire polymerization between 15–25° C.After 30 minutes into the polymerization, vinyl pyrrolidone is pumpedinto the autoclave. After consumption of the initial charge of VDF andHFP, VDF and HFP are added to the autoclave at the stoichiometric ratioto maintain a reactor pressure of 50–130 psig. In total, 25 kg of VDF,11 kg of HFP, and 2.7 kg of vinyl pyrrolidone is added to the autoclave.After consumption of all monomers, the autoclave is vented, and thewater removed. The polymer is purified by extracting twice with 20liters of methanol followed by drying in vacuo.

Example 2 Synthesis of poly(vinylidenefluoride-co-hexafluoropropene-co-vinyl pyrrolidone), Molar Ratio 80/18/2by Atom Transfer Polymerization

To a 2.5 gallon stainless steel autoclave equipped with agitation isadded copper bromide (28g, 0.195 mole), 2,2′-bipyridine (60.9 g, 0.39mole), and 1,2-diiodoethane (55 g, 0.195 mole). The autoclave is purgedwith argon to remove all oxygen. CO₂ is introduced to reach a pressureof 1200 psig and the autoclave thermostated to ambient temperature. Theautoclave is then charged with 1 kg of VDF and 528 g of HFP. Thetemperature is raised to 40° C. and the reaction allowed to proceed for20 hours. Vinyl pyrrolidone is added (43.4 g) and the polymerizationallowed to proceed for 11 more hours. After venting the autoclave thepolymer is dissolved in 5 liters of acetone and then isolated byprecipitation into methanol.

Example 3 Preparation of a Drug Eluting Stent Coating Using the Polymerof Example 1

A polymer solution containing between about 0.1 mass % and about 15 mass%, for example, about 2.0 mass % of PBMA and the balance, a solventmixture of acetone and cyclohexanone, the solvent mixture containingabout 60 mass % of acetone and about 40 mass % of xylene is prepared.The solution is applied onto a stent to form a primer layer. To applythe primer layer, a spray apparatus, such as an EFD 780S spray nozzlewith a VALVEMATE 7040 control system (manufactured by EFD, Inc. of EastProvidence, R.I.) can be used. The EFD 780S spray nozzle is anair-assisted external mixing atomizer. The composition is atomized byair and applied to the stent surfaces. During the process of applyingthe composition, the stent can be optionally rotated about itslongitudinal axis, at a speed of 50 to about 150 rpm. The stent can alsobe linearly moved along the same axis during the application.

The poly(butyl methacrylate) (PBMA) solution can be applied to a 1 2-mmsmall VISION stent (available from Guidant Corporation) in a series of10-second passes, to deposit, for example, 10 μg of coating per spraypass. Between the spray passes, the stent is dried for about 10 secondsusing flowing air with a temperature of about 60° C. Five spray passescan be applied, followed by baking the primer layer at about 80° C. forabout 1 hour. As a result, a primer layer can be formed having a solidscontent of about 50 μg. “Solids” means the amount of the dry residuedeposited on the stent after all volatile organic compounds (e.g., thesolvent) have been removed.

A drug-containing formulation can be prepared containing:

(a) between about 0.1 mass % and about 15 mass %, for example, about 2.0mass % of the polymer of example 1;

(b) between about 0.1 mass % and about 2 mass %, for example, about 0.8mass % of an active agent, for example, everolimus; and

(c) the balance, a solvent mixture of acetone, the solvent mixturecontaining about 70 mass % of acetone and about 30 mass % ofcyclohexanone.

In a manner identical to the application of the primer layer, nineteenspray passes is performed, followed by baking the drug-polymer layer atabout 50° C. for about 2 hours, to form the drug-polymer reservoir layerhaving a solids content between about 30 μg and 750 μg, for example,about 190 μg, and a drug content of between about 10 μg and about 250μg, for example, 50 μg.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. A biocompatible copolymer comprising fluorinated monomers andhydrophilic monomers, wherein the copolymer has a structure of formulaI:

wherein the copolymer is generated by direct polymerization of thefluorinated monomers and the hydrophilic monomers.
 2. The biocompatiblepolymer of claim 1,

wherein the strength fluoro monomer is selected from the groupconsisting of —CF₂—CF₂—, —CH₂—CF₂—, —CH₂—CHF—, —CF₂—CHF—, —CHF—CHF—, or—CF₂—CRF— where R can be phenyl, cyclic alkyl, heterocyclic, heteroaryl,fluorinated phenyl, fluorinated cyclic alkyl, or fluorinatedheterocyclic, wherein the flexibility fluoro monomer is selected fromsubstituted fluorinated ethylene monomers that bear a substituent,wherein the hydrophilic monomer is selected from the group consisting ofvinyl monomers that bear a pyrrolidone group(s), carboxylic acidgroup(s), sulfonic acid group(s), sulfone group(s), amino group(s),alkoxy group(s), amide group(s), ester group(s), acetate group(s),poly(ethylene glycol) group(s), poly(propylene glycol) group(s),poly(tetramethylene glycol) group(s), poly(alkylene oxide) group(s),hydroxyl group(s), or a substituent that contains a charge or one ofpyrrolidone group(s), carboxylic acid group(s), sulfone group(s),sulfonic acid group(s), amino group(s), alkoxy group(s), amide group(s),ester group(s), acetate group(s), poly(ethylene glycol) group(s),poly(propylene glycol) group(s), poly(tetramethylene glycol) group(s),poly(alkylene oxide) group(s), hydroxyl group(s), and combinationsthereof.
 3. The biocompatible copolymer of claim 2,l wherein theflexibility monomer can be —CF₂—CRF—, —CHF—CRF—, and —CF₂—CRH—, orcombinations thereof in which R is selected from the group consisting oftrifluoromethyl, F, Cl, Br, I, short chain alkyl groups from C₂ to C₁₂,fluorinated short chain alkyl groups from C₂ to C₁₂, and combinationsthereof.
 4. The biocompatible copolymer of claim 1, wherein thehydrophilic monomer is selected from the group consisting of vinylpyrrolidone, hydroxyethyl methacrylate, hydroxypropyl methacrylate,methyl vinyl ether, alkyl vinyl ether, vinyl alcohol, methacrylic acid,acrylic acid, acrylamide, N-alkyl acrylamide,hydroxypropylmethacrylamide, vinyl acetate, 2-sulfoethyl methacrylate, 3-sulfopropyl acrylate, 3 -sulfopropyl methacrylate, PEG-methacrylate,2-aminoethyl methacrylate hydrochloride, N-(3-aminopropyl)methacrylamidehydrochloride, 2-N-morpholinoethyl methacrylate, vinylbenzoic acid,vinyl sulfonic acid, styrene sulfonates, a monomer that bears a charge,and combinations thereof.
 5. The biocompatible copolymer of claim 2,wherein the hydrophilicity monomer is selected from the group consistingof vinyl pyrrolidone, hydroxyethyl methacrylate, hydroxypropylmethacrylate, methyl vinyl ether, alkyl vinyl ether, vinyl alcohol,methacrylic acid, acrylic acid, acrylamide, N-alkyl acrylamide,hydroxypropylmethacrylamide, vinyl acetate, 2-sulfoethyl methacrylate,3-sulfopropyl acrylate, 3-sulfopropyl methacrylate, PEG-methacrylate,2-aminoethyl methacrylate hydrochloride, N-(3-aminopropyl)methacrylamidehydrochloride, 2-N-morpholinoethyl methacrylate, vinylbenzoic acid,vinyl sulfonic acid, styrene sulfonates, a monomer that bears a charge,and combinations thereof.
 6. The biocompatible copolymer of claim 2having a structure of any of formulae II–IV:


7. The biocompatible copolymer of claim 2, wherein the strength fluoromonomer is in the range from about 60 mole % to about 90 mole %, whereinthe flexibility fluoro monomer is in the range from above 0 mole % toabout 40 mole %, and wherein the hydrophilic monomer is in the rangefrom above 0 mole % to about 20 mole %.